Novel process

ABSTRACT

A wet granulation process in which a pharmaceutical substance is granulated using a granulating fluid which is a halogenated hydrocarbon which has a normal boiling point below ambient temperature, for example 1,1,1,2-tetraflouroethane, under a pressure sufficient to maintain the halogenated hydrocarbon in a liquid state. A process in which the halogenated hydrocarbon is re-cycled, and suitable equipment for performing the process is also described.

[0001] This invention relates to a novel process, being a novel processfor pharmaceutical granulation.

[0002] Granulation is a process well known in the pharmaceuticalindustry, involving the preparation of aggregates (“granules”) of fineparticles of materials. Such granules are often subsequently compactedto form solid dosage forms, e.g. tablets and pills, although somepharmaceutical formulations are dispensed as granules, e.g. in a sachetfor make up with water or for direct oral administration. Formulationsof pharmaceutical powders are granulated for a variety of reasonsfalling into two main classes; processing and formulation. Processingreasons are exemplified by the need for densification and aggregation. Adense, granular material will flow more evenly and fill dies on highspeed tablet machines better and with greater consistency than a simplemixture. An aggregated material will not tend to demix on storage ortransport, and fine components will not be lost to extraction systemswhen transported through packing or processing plant. Granulation isdiscussed in many standard textbooks on pharmaceutical chemistry, forexample “The Theory and Practice of Industrial Pharmacy”, Lachman,Lieberman & Kanig, (1986).

[0003] One method of making granules is so called “wet granulation”. Inits simplest form, wet granulation involves the addition of agranulating fluid, commonly water, finctioning as a granulating fluid,to a stirred essentially insoluble powder comprising the materials to begranulated. The stirring is essential to distribute water homogeneouslythrough the powder bed. As the proportion of water rises, particles willabsorb or adsorb water to the point where the individual particles arefirst saturated and then coated. After this point, liquid bridges willform between particles. At a critical point, the water content will besuch that surface tension alone will pull groups of particles intoaggregates. At this point water addition is halted and the powder can bedried. If the drying and subsequent handling is done with care, theaggregates will retain their integrity, giving a material which is bothdenser and more free flowing than the original material.

[0004] The granules can be made much more robust by the introduction ofdissolved material into the liquid bridges, either by dissolvingmaterial into the granulating liquid prior to use, or by ensuring thatthe granulate (or a constituent thereof) is soluble or partiallysoluble. There are many variations on this theme, and solubleconstituents (binders) can be simple polymers (PVP, starch gels) or mayhave more complex functions (enteric coating polymers).

[0005] Water has the advantage that it readily facilitates bridgingbetween particles which assists agglomeration of the particles to formgranules, but a major problem with wet granulation using water as thegranulating fluid is that of drying. Removal of water from the wetgranules can require large amounts of energy and can take a long time.Wet granulation has also been carried out with organic solvents orwater-organic solvent mixtures, but even organic solvents require energyto remove them from granules, and they present fire or toxicity hazards.

[0006] It is an object of this invention to provide an improved wetgranulation process which, in part at least, solves the problems of suchknown wet granulation processes.

[0007] It is known to use organic solvents for various processes in themanufacture of pharmaceutical formulations. For example GB-A-2197197discloses the compaction of tablets in the presence of organichalogenated hydrocarbons, the examples illustrating processes at ambientor elevated temperatures. JP-07-265682 discloses the preparation ofspherical particles by suspending powdered organic compounds in ahalogenated solvent and granulating the material, the examplesillustrating use of carbon tetrachloride or dichlorobenzene and water asa binder.

[0008] According to this invention a wet granulation process is providedwherein a pharmaceutical substance is granulated using a granulatingfluid which is a halogenated hydrocarbon which has a normal boilingpoint below ambient temperature, under a pressure sufficient to maintainthe halogenated hydrocarbon in a liquid state.

[0009] This invention therefore provides the use of a halogenatedhydrocarbon which has a normal boiling point below ambient temperatureas a granulating fluid in a wet granulation process for a pharmaceuticalsubstance.

[0010] In the present invention the halogenated hydrocarbon is a gas atambient temperature and atmospheric pressure, and is kept liquid duringthe granulation process by application of elevated pressure. Thepressure at which the halogenated hydrocarbon becomes liquid bycompression at ambient temperature is termed “Pv”, that is, the vapourpressure.

[0011] In more detail the present invention provides a process for thegranulation of a pharmaceutical substance in which;

[0012] a pharmaceutical substance in particulate form is mixed with aliquid halogenated hydrocarbon which has a normal boiling point belowambient temperature,

[0013] the mixture is agitated to form granules comprising aggregates ofthe particles of the pharmaceutical substance, and

[0014] the halogenated hydrocarbon is separated from the so-formedgranules.

[0015] In the process of this invention the halogenated hydrocarbonwhich is a gas at room temperature and atmospheric pressure is keptliquid by pressure so that the process may be operated without the needfor refrigeration. For example a suitable boiling point for the liquidhalogenated hydrocarbon is −10 to −150° C., preferably −10 to −50° C.,at atmospheric pressure. Preferably the halogenated hydrocarbon is asubstance that can be kept liquid at temperatures up to 40° C. byapplying pressures of up to 10 atmospheres. Such working conditions arerelatively easy to achieve usipg conventional chemical engineeringtechnology. The process of the invention may be operated at such apressure, e.g. in a suitable pressure vessel.

[0016] Such halogenated hydrocarbons have the advantages as media forthe process of the invention that they are odourless and colourlessgases at ambient temperature, liquefy at around 5 bar at ambienttemperature, are chemically inert, are non-flammable, are non-toxic, arenon-corrosive, have a neutral pH and are approved for use in foodprocessing by many regulatory authorities. A mixture of halogenatedhydrocarbons may be used to achieve a convenient boiling point. Thehalogenated hydrocarbon or mixtures thereof may be mixed with other lownormal boiling point compounds, e.g. low boiling point hydrocarbons suchas C₁₋₅ alkanes, e.g. propanes and/or butanes. Suitably such mixturesmay form azeotropes so that the mixture itself may be separated from thegranules by evaporation at a constant temperature without fractionation.These halogenated hydrocarbons also have the advantage that they areeasy to handle and re-cycle compared with higher boiling pointgranulating liquids, as they can be removed from a vessel containingthem simply by reducing the pressure, allowing the halogenatedhydrocarbon to evaporate, and then re-liquefying it with a compressor.

[0017] Suitably the halogenated hydrocarbon is a compound of formulaC_(n)H_(m)F_(p)Cl_(r), where n and m are whole numbers, p and r are zeroor whole numbers provided that both p and r are not zero and that(m+p+r) equals 2n+2. The halogenated hydrocarbon is preferably afluorinated non-chlorinated hydrocarbon. Preferably the halogenatedhydrocarbon is a compound of formula C_(n)H_(m)F_(p) where n, m and pare whole numbers and (m+p) equals 2n+2.

[0018] The lower and upper limits of n are determined more by thepractical considerations of achieving the above-mentioned liquefactioncharacteristics, and typically n is between 1 and 10. Preferably in sucha compound n is 2 or 3, preferably 2 so that the compound is an ethanederivative, preferably p is 3, 4 or 5, especially 4 so that the compoundis a tetrafluoroethane. A particularly preferred fluorinated hydrocarbonis 1,1,1,2-tetrafluoroethane (bp. −26° C., critical temperature +101°C.). This material is commercially available (from ICI) under the nameR134A, and is otherwise known for use as a refrigerant. R134A is1,1,1,2-tetrafluoroethane sold to a high purity specification andcontains no significant amounts of other fluorocarbons or organicsolvents. The highest specification 1,1,1,2-tetrafluoroethane that issold is P134A, “P” standing for pharmaceutical grade, e.g. as used as apropellant in inhalers. It is not believed to be necessary to use theP134A grade of 1,1,1,2-tetrafluoroethane in the process of thisinvention.

[0019] Other suitable halogenated hydrocarbons include fluoroform,monofluoromethane, difluoromethane, trifluoromethane, pentafluoroethane,1,1,1-trifluoroethane, 1,1-difluoroethane,1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2,2,3,3-heptafluoropropane,1,1,1,3,3,3-hexafluoropropane, 1,1,1,2,2-pentafluoropropane,1,1,1,2,2,3-hexafluoropropane, 1,1,2,2,3,3-hexafluoropropane, and1,1,1,2,3,3-hexafluoropropane. A suitable fluorinated and chlorinatedhydrocarbon is difluorodichloromethane. Some other examples ofhalogenated hydrocarbons include 2,2-difluoropropane (bp. −0.6° C.) and1,1-difluoroethane (bp. −24.7° C.)

[0020] The process of the present invention appears to be suitable forall types of drug substance, e.g. antibiotics, antidepressants,anti-inflammatories, antiviral agents, analgesics, substances for thetreatment of diabetes etc.

[0021] In pharmaceutical granules the drug substance is normally mixedwith standard excipients such as one or more of a filler, a lubricant, adisintegrant, a glidant, a colourant, a flavour or flavour modifier etc.Examples of these are well known and are listed in standard texts suchas for example Lachman, Lieberman & Kanig (op cit.) and the process ofthe invention appears to be suitable for the granulation ofpharmaceutical substances which comprise a drug substance mixed with oneor more of such excipients.

[0022] It may be possible to use the process of this invention forgranulating the substance without a binder, but preferably in theprocess the pharmaceutical substance includes a binder. Suitable bindersare known and listed in for example the above-mentioned standard texts.A preferred binder is one that is soluble in the halogenatedhydrocarbon. As the process of the invention can be operated in a mannerthat recycles the halogenated hydrocarbon over the binder to re-saturatethe recycled halogenated hydrocarbon with the binder so as to transferit to the pharmaceutical substance, the process can operate even whenthe binder is only slightly soluble in the halogenated hydrocarbon, forexample at solubilities of 1 % w:w, 0.25% w:w or even lower of thebinder in the halogenated hydrocarbon.

[0023] Preferred binders therefore include low molecular weight (e.g.<10,000) polymeric binders, for example polyethers; cellulose-basedpolymers such as methylcelluloses, ethylcelluloses;polyvinylpyrrolidones (e.g. Kollidons), acrylate and methacrylatepolymers for example the polymer materials available from Rbhm GmbHunder the trade mark “Eudragit”, e.g. Eudragit RS, Eudragit E, etc.,polyacrylamides, vinylic polymers such as polyvinyl achohols, estersetc.

[0024] The proportion of binder in the granulated product made by theprocess of this invention may be the same as would be used in aconventional granulation process and a suitable proportion may bedetermined by experiment. For example in some applications, such as whengranulation is used to taste mask a highly soluble drug substance, thegranulated product may comprise 50% w:w or more of the granulatedproduct, though other applications may use less binder. The process ofthe invention itself does not appear to impose or require any limits onthe proportion of binder in the granulated product.

[0025] A binder when used may be made into a mixture with thepharmaceutical substance in a number of ways. For example the binder maybe pre-mixed with the particles of pharmaceutical substance, and thenthe halogenated hydrocarbon may be mixed with this pre-mix. Some commonbinders are available in solution form, and they may be pre-mixed withthe substance in this form. Typically this might be a batch process. Forexample the binder may be dissolved or suspended in the halogenatedhydrocarbon, and this solution or suspension may be mixed with thepharmaceutical substance.

[0026] In a preferred way, the halogenated hydrocarbon is passed overthe binder in a saturator vessel to form a solution, preferably asaturated solution, of the binder and this solution is then introducedto the pharmaceutical substance in a suitable granulator vessel. Thehalogenated hydrocarbon may then be removed by evaporation from themixture of substance and binder and then re-liquefied e.g. by elevatingthe pressure and/or lowering the temperature, in a condenser, and passedover the binder again to dissolve further binder, preferably to bere-satuiated with binder, then this recycled solution is added to thesubstance in the granulator vessel, i.e. in a cyclic process, until allor sufficient binder has been mixed into the pharmaceutical substance.

[0027] Such a recycling process, in which the halogenated hydrocarbon isre-ccirculated via a condenser and pump, passed through a saturatorloaded with binder, and then passed back into the granulator may beadvantageous when the solubility of the binder in the halogenatedhydrocarbon is low, in which case such a recycling process can steadilytransfer a relatively insoluble binder into the granulator vessel.

[0028] It may be possible to increase the solubility of binders byincorporating entraining or modifying solvents into the halogenatedhydrocarbon, and such a mixture of halogenated hydrocarbon and solventcan be handled in the same way as a pure halogenated hydrocarbon in theprocess of this invention. However purging of the product granules usingpure halogenated hydrocarbon may be required to remove traces of suchsolvents. If such a mixture is used preferably the mixture is anazeotropic solvent mixture, so that the solvent may be removed atambient pressure and temperature together with the halogenatedhydrocarbon. Examples of suitable entraining or modifying solventsinclude water, C1-10 aliphatic alcohols, ketones or esters, typically ifused comprising 0.5-10 % v:v of the halogenated hydrocarbon, solventmixture. For example polymethacrylate binders such as the Eudragit™materials are soluble in propanol, acetone and propanol—acetonemixtures.

[0029] The particle sizes, grades, .size distribution etc. for thepharmaceutical substance, e.g. a drug substance, excipients and binder,if used, may be similar or identical to those used in conventional wetgranulation processes. Typically such materials are provided forgranulation as powders with a particle size of ca. 500 microns or less,and the process of granulation generates agglomerated granules with agranule size larger than this.

[0030] The ratio of halogenated hydrocarbon to pharmaceutical substanceto be granulated does not appear to be critical and the process appearsto be operable over a wide range of ratios ranging from a fluidsuspension through a viscous moistened, e.g. dough-like mass to a light“crumb” (term of the art). However a highly viscous mass may have thedisadvantage of needing a high power requirement to agitate andthoroughly mix the ingredients, and an excess of the halogenatedhydrocarbon will take longer to separate from the mixture than a smalleramount. Typically the mixture of pharmaceutical substance andhalogenated hydrocarbon may contain 0.01 to 99.9% w:w, for example <5 to95% w:w of the halogenated hydrocarbon. Suitable ratios, and otheroperating conditions such as processing time, operating power,granulator equipment construction etc., for any particularpharmaceutical substance may be determined experimentally by techniqueswell known to those skilled in the art of pharmaceutical granulation.For example progress toward completion of the granulation process may bedetermined simply by removal and inspection of a sample of the mixturefrom the mixing vessel in which the process is being performed.Alternatively progress may be followed by monitoring power consumptionof the agitator, e.g. the stirrer motor of the granulation vessel.Alternatively, infra red, acoustic and image analysis or othernon-intrusive techniques may also be employed.

[0031] As the halogenated hydrocarbon has a normal boiling point belowroom temperature it is preferably separated from the granules byreduction of the pressure so that the halogenated hydrocarbon evaporatesoff from the granules. This evaporation is preferably performed in aclosed system so the evaporated halogenated hydrocarbon may be led awayalong a flow line to a suitable receiver e.g. via a condenser asabove-mentioned. The reduction of pressure may be controlled so thatsmooth evaporation of the halogenated hydrocarbon occurs. Thereafterpurging e.g. with nitrogen can ensure removal of further traces of thehalogenated hydrocarbon if necessary.

[0032] After separation of the halogenated hydrocarbon from thegranules, these may be further processed in other ways. For example theymay be subdivided, screened etc. before ultimate use e.g. compactioninto tablets etc. Such further processing may be identical or similar tofurther processing as used with conventional wet granulation processes.

[0033] On an industrial scale, conventional granulating equipment mayconveniently be adapted to run the process of the invention. For examplea generally conventional granulator may be provided with a closure,means to maintain a suitable pressure within it, means to introduce thehalogenated hydrocarbon, and means to remove the halogenatedhydrocarbon.

[0034] Such a granulator may comprise a pressurised vessel based upon aconventional sigma blade, heavy duty planetary mixer, or high intensitymixer (Fielder, Collette), and which may be capable of granulating 100to 200 kg. of material, depending on the density of the powders and theconsistency of the resulting wetted mass. For bench scale work asuitable granulator may be based on a small scale Caleva spheronizer.The spheronizer disk may be removed and replaced with a double scimitarchopping blade or impeller after the conventional model. Other methodsof agitation, such as ultrasonic agitation may be used. A closure may befitted on the pressure vessel, equipped with inlet and outlet ports(e.g. ⅛ Swage-Lok). The lid may also be also fitted with a window andpressure relief valve (typically 10 bar spec). The equipment may also befitted with a power consumption monitor, and may be jacketed fortemperature control.

[0035] In use, binder e.g. a polymer as mentioned above may be dissolvedin the halogenated hydrocarbon in an agitated, e.g. stirred, dissolutionvessel equipped with a pressure gauge. halogenated hydrocarbon may bepumped into this vessel from a separate source vessel until a suitableliquid level is reached, and the halogenated hydrocarbon is saturatedwith the binder, then the saturated solution may be pumped into thegranulator vessel. The dissolution vessel may be jacketed in common withthe mixer vessel to ensure that temperature (and Pv) are the same.

[0036] A preferred configuration of equipment to perform the process ofthis invention comprises;

[0037] a source of halogenated hydrocarbon (optionally mixed with one ormore of the above-mentioned solvents),

[0038] means such as a pump to transfer halogenated hydrocarbon from thesource to a saturator vessel,

[0039] a saturator vessel, in use being loaded with a binder, and ableto bring halogenated hydrocarbon and binder into contact to generate asolution of the binder in the halogenated hydrocarbon,

[0040] means such as a pump to transfer the solution of binder in thehalogenated hydrocarbon to a granulator vessel and to pressurise thegranulator vessel,

[0041] a granulator vessel in which the pharmaceutical substance inparticulate form to be granulated is mixed with the liquid halogenatedhydrocarbon to form granules comprising aggregates of the particles ofthe pharmaceutical substance, the vessel being equipped with means ofcontrolling the pressure of the granulating fluid inside it.

[0042] means to remove the halogenated hydrocarbon from the granulatorvessel in a gaseous state,

[0043] a compressor to compress the gaseous halogenated hydrocarbon,

[0044] a condenser by which the halogenated hydrocarbon is converted toa liquid state,

[0045] means to return the liquid halogenated hydrocarbon to the source.

[0046] Optionally this equipment may include a trap situated upstream ofthe compressor to remove entrained material from the flow of gaseoushalogenated hydrocarbon.

[0047] The present invention therefore provides a granulation processwherein a pharmaceutical substance is granulated using such equipment.

[0048] The present invention also provides a granulated pharmaceuticalsubstance obtainable by a process as described herein. Such a granulatedsubstance may contain a trace of residual fluorinated hydrocarbon.

[0049] The invention will now be described by way of example only withreference to:

[0050]FIG. 1 which shows schematically a configuration of equipment forperforming the process of this invention.

[0051]FIG. 2 which shows particulate material before granulation usingthe process of this invention.

[0052]FIG. 3 which shows the material of FIG. 2 after granulation usingthe process of this invention.

[0053] Referring to FIG. 1, a schematic configuration of equipment isshown. This comprises a source (10) of halogenated hydrocarbon being apressurised tank. The halogenated hydrocarbon used is R134A, acommercially available mixture of 1,1,1,2-tetrafluoroethane and otherorganic solvents, available from ICI. R134A is a gas at roomtemperature, but can be easily liquefied at a pressure of 10 bar attemperatures as high as 40° C. From the tank (10) the R134A is pumped bypump (11) via line (12) to a saturator vessel (13).

[0054] Saturator vessel (13) is a conventional extraction vessel, and isloaded with a known polymeric binder such as a Eudragit™, for exampleEudragit RS™ or Eudragit E™, or a known polyvinylpyrrolidone polymer,e.g. as commercially available under the name “Kollidon™”. In thesaturator (13) the halogenated hydrocarbon pumped into the saturator(13) and the binder are brought into contact, and may be agitated bystirrer (14), so that the binder dissolves in the halogenatedhydrocarbon. The solution of binder in the halogenated hydrocarbon maybe saturated or under-saturated.

[0055] From the saturator (13) the continued action of the pump (11)transfers the saturated solution of the binder in the halogenatedhydrocarbon via line (15) into the granulator vessel (16).

[0056] The granulator vessel (16) is a granulator vessel of generallyconventional construction, e.g. of the conventional sigma blade, heavyduty planetary mixer, or high intensity mixer (Fielder, Collette) type,and may typically be capable of granulating 100 to 200 kg. of material.The vessel (16) is provided with a closure etc. to enable a pressure ofca. 10 bar, i.e. sufficient to keep the R134A in a liquefied state atambient temperature to be maintained. A pharmaceutical substance inparticulate form to be granulated has previously been loaded into thevessel (16). This substance may be a typical mixture of a drug substanceand excipients (with the exception of a binder insofar as this isprovided as the above-mentioned solution). The mixture of pharmaceuticalsubstance and the saturated solution is agitated in the vessel by themixing blade (17). The vessel (16) is provided with a pressure reliefvalve (18) for safety.

[0057] Gaseous R134A evaporates off from the mixture in the vessel (16)and is bled off via line (19), pressure being regulated by means of thepressure regulator (110). The vapour is passed through trap (111) toremove e.g. solid particles etc entrained in the vapour, and is thencompressed by compressor (112), and condensed by condenser (113) backinto liquid form. The liquid R134A is then transferred back into thevessel (10), from whence it can be recycled into granulator vessel againvia line (12), pump (11) and saturator (13).

[0058] As this recycled R134A is passed through the saturator (13) itwill become re-saturated with the binder and thereby transfers morebinder into vessel (16), so that the amount of binder in granulator (16)gradually builds up to an appropriate level to form the granules. Asteady state is achieved in which an approximately constant level ofliquid R134A is maintained in granulator (16) by controlled bleeding outvia line (19) and controlled re-cycling of the R134A.

[0059] The progress of granulation of the substance in the granulatorvessel (16) may be monitored by conventional methods, e.g. withdrawal ofa sample from granulator vessel (16) or by monitoring of powerconsumption of the mixer blade (17). When granulation is consideredcomplete the re-cycling of R134A is stopped, and remaining R134A isseparated from the granules in granulator vessel (16) by reduction ofpressure in the granulator vessel (16) and bleeding the remaining R134Aout of granulator (16) via line (19).

[0060] If for example a mixture of a halogenated hydrocarbon and anorganic solvent is used as the granulating fluid, it might be necessaryto purge residual traces of the organic solvent from the granulatorvessel (16) by passing pure halogenated hydrocarbon through the vessel(16). The system may also include a by-pass line (not shown) by whichhalogenated hydrocarbon granulating fluid may be introduced directlyinto the granulator vessel (16) without passing through the saturator(13) to enable the granulator vessel (16) to be pressurised with thehalogenated before introducing the binder to vessel (16).

[0061] After this the pressure in granulator (16) may be reduced toatmospheric, the halogenated hydrocarbon or R134A itself purged withair, and the so-formned granules may be removed from the granulator (16)and further processed e.g. by a conventional compaction process to formtablets.

Laboratory Example

[0062] An inert filler material, manitol (Perlitol 200 SD, Roquette) wasloaded into a vessel (For example, a 100 cm³ Pamasol™ Aerosol TestGlasses, type P200/002) fitted with a gas tight valve together with anappropriate amount of polymer binder, to a total weight of 2.0 g of themixed filler and binder. The vessel was charged with 40 cm3 of R134A,and thoroughly mixed. The vessel was then placed in an ultrasonic bathat 40° C. for 15 minutes to ensure dissolution of the polymer, thenshaken well. The vessel was returned to the ultrasonic bath for afurther 15 minutes. The ultrasound was then turned off, the pressurevalve was opened and the R134 was allowed to evaporate. The aggregatedmaterial was then recovered. No physical work was put into the granuleand no post granulation size reduction carried out.

[0063] The following polymeric binder materials were used:

[0064] Kollidon 12™

[0065] Kollidon 17™

[0066] Eudragit RS PO™

[0067] Eudragit E 100™

[0068] Erkopol B-1.5™

[0069] Erkopol B-17™

[0070] These were all used at 10, 20 and 30% w/w of the overallmannitol—binder mixture.

[0071] The degree of granulation was assessed by shaking the materialsover a pair of nested sieves, 1000 and 500 microns. 100% of Perlitol 200sd passes through a 500 micron sieve. The % retained >500 microns givesa measure of agglomeration. % retained % retained % retained % retained1000 mic. 500 mic. Base >500 mic. Kollidon 12 @ 10% 21.5 2.7 75.9 24.1Kollidon 12 @ 20% 17.0 17.4 65.6 34.4 Kollidon 12 @ 30% 55.7 10.2 34.066.0 Kollidon 17 @ 10% 1.0 2.8 96.2 3.8 Kollidon 17 @ 20% 8.1 1.4 90.59.5 Kollidon 17 @ 30% 17.0 24.4 58.6 41.4 Eudragit RS100PO 10% 57.2 5.537.3 62.7 Eudragit RS100PO 20% 51.8 10.1 38.1 61.9 Eudragit RS100PO 30%69.5 10.6 19.9 80.1 Eudragit E100 10% 35.5 19.2 45.2 54.8 Eudragit E10020% 56.2 18.0 25.8 74.2 Eudragit E100 30% 46.6 20.7 32.7 67.3

[0072] Referring to FIGS. 2 and 3, these respectively show Perlitol 200SD, (Roquette) in particulate form both prior to granulation in thelaboratory example described above (FIG. 2) and after granulation using30% Eudragit RS100PO as binder. It is seen that the particulate materialhas been converted into large granules in the process of the invention.

[0073] Erkopol materials were granulated so effectively that in someexperiments the product had to be dug out of the vessel at these levelsof polymer addition.

1. A wet granulation process wherein a pharmaceutical substance isgranulated using a granulating fluid which is a halogenated hydrocarbonwhich has a normal boiling point below ambient temperature, under apressure sufficient to maintain the halogenated hydrocarbon in a liquidstate.
 2. A process according to claim 1 characterised in that; apharmaceutical substance in particulate form is mixed with a liquidhalogenated hydrocarbon which has a normal boiling point below ambienttemperature, the mixture is agitated to form granules comprisingaggregates of the particles of the pharmaceutical substance, thehalogenated hydrocarbon is separated from the so-formed granules.
 3. Aprocess according to claim 1 or 2 characterised in that the halogenatedhydrocarbon has a normal boiling point +20° C. to −150° C. atatmospheric pressure.
 4. A process according to any one of theproceeding claims characterised in that the halogenated hydrocarbon is acompound of formula C_(n)H_(m)F_(p)Cl_(r), where n and m are wholenumbers, p and r are zero or whole numbers provided both p and r are notzero and (m+p+r) equals 2n+2.
 5. A process according to claim 4characterised in that the halogenated hydrocarbon is a compound offormula C_(n)H_(m)F_(p) where n, m and p are whole numbers and (m+p)equals 2n+2.
 6. A process according to claim 5 characterised in that nis 2 or 3, and p is 3, 4 or
 5. 7. A process according to claim 6characterised in that the halogenated hydrocarbon is1,1,1,2-tetrafluoroethane.
 8. A process according to any one of thepreceding claims characterised in that the pharmaceutical substanceincludes a binder.
 9. A process according to claim 8 characterised inthat the binder is soluble in the halogenated hydrocarbon.
 10. A processaccording to claim 8 or 9 characterised in that the binder is a lowmolecular weight polymeric binder.
 11. A process according to claim 8, 9or 10 characterised in that the binder is selected from polyethers,cellulose-based polymers, polyvinylpyrrolidones, acrylate andmethacrylate polymers.
 12. A process according to any one of claims 9 to11 characterised in that the binder is pre-mixed with the particles ofpharmaceutical substance, and then the halogenated hydrocarbon is mixedwith this pre-mix.
 13. A process according to any one of claims 8 to 11characterised in that the binder is dissolved or suspended in thehalogenated hydrocarbon, and this solution or suspension is mixed withthe pharmaceutical substance.
 14. A process according to claim 13characterised in that the halogenated hydrocarbon is passed over thebinder in a saturator vessel to form a solution of the binder; thissolution is then introduced to the pharmaceutical substance in a vessel,halogenated hydrocarbon is then evaporated from the mixture of substanceand binder, then re-liquefied and passed over the binder again todissolve further binder, then this recycled solution of binder in thehalogenated hydrocarbon is added to the substance in the granulatorvessel, in a cyclic process.
 15. A process according to any one of thepreceding claims characterised in that entraining or modifying solventsare incorporated into the halogenated hydrocarbon.
 16. A processaccording to any one of the preceding claims characterised in that thehalogenated hydrocarbon is separated from the granules by reduction ofthe pressure so that the halogenated hydrocarbon evaporates off from thegranules.
 17. Equipment to perform the process according to any one ofthe preceding claims, comprising; a source of halogenated hydrocarbon,means to transfer halogenated hydrocarbon from the source to a saturatorvessel, an extraction vessel, in use being loaded with a binder, andable to bring halogenated hydrocarbon and binder into contact togenerate a solution of the binder in the halogenated hydrocarbon, meansto transfer the solution of binder in the halogenated hydrocarbon to agranulator vessel, a granulator vessel in which the pharmaceuticalsubstance in particulate form to be granulated is mixed with the liquidhalogenated hydrocarbon to form granules comprising aggregates of theparticles of the pharmaceutical substance, means to remove thehalogenated hydrocarbon from the granulator vessel in a gaseous state, acompressor to compress the gaseous halogenated hydrocarbon, a condenserby which the halogenated hydrocarbon is converted to a liquid state,means to return the liquid halogenated hydrocarbon to the source.
 18. Agranulated pharmaceutical substance obtainable by a process according toany one of claims 1-16.